Few simple sex differences were found in this study, as men and women generally did not differ in most mood, physiological, sensory, and performance responses to nicotine, and in the reinforcement measure. Notable exceptions were the increases in one measure of reward (“satisfying”) and in incentive salience (“want more”) due to nicotine in men versus women. These findings are partly consistent with prior research suggesting that men and women differ in sensitivity to nicotine’s rewarding (as well as reinforcing) effects but not to most other effects (Benowitz and Hatsukami 1998
; Perkins 1996
; in press
; Perkins et al., 1999
). The current results extend this research by demonstrating, for the first time to our knowledge, that at least some of this sex difference in reward precedes the onset of dependence due to chronic nicotine exposure via smoking. Thus, male and female teens may differ in sensitivity to some of the rewarding effects of nicotine upon initial exposure, such as during early cigarette experimentation.
However, we did not observe an overall sex difference in nicotine reinforcement via the choice procedure using 1.25 μg/kg/spray. This observation is consistent with an earlier study of nonsmokers using 1.5 μg/kg/spray (Perkins et al. 2001b
), but it is contrary to a study of nonsmokers using 2.5 μg/kg/spray that did find greater choice in men versus women (Perkins et al., 1997
). As with many individual differences in drug responses (e.g., McCaul et al., 1991
), sex differences in nicotine reinforcement appear to depend strongly on the drug dose. On the other hand, we did find greater nicotine choice in men versus women among those with prior marijuana use but not among those without marijuana use. Conceivably, prior marijuana use may heighten sensitivity to nicotine, at least in men, such that sex differences in reinforcement are seen at lower nicotine doses, in addition to the broader sex difference in reinforcement at higher nicotine doses (Perkins et al., 1997
). Moreover, these results may suggest that some sex differences in nicotine responses are moderated by other individual difference factors, and focusing only on simple interactions of dose X sex may overlook important complex interactions involving sex (see Perkins, 2004
; Ray et al., 2006
Use of other drugs was generally not related to initial sensitivity to acute nicotine via nasal spray. Exceptions were the increase in “satisfying” (reward) due to nicotine among those with prior marijuana use, the increase in “feel the effects” due to nicotine among those with prior tobacco use (), and the lack of improvement in rapid information processing due to nicotine among those with higher alcohol intake (). The prevalence or amount of other drug use was relatively limited in this sample (), and greater variability in other drug use could show more influence on initial sensitivity to nicotine. Nevertheless, within the limitations of this study, these results generally do not support the notion that other drug use produces clear cross-tolerance or cross-sensitization to nicotine in humans.
Similarly, parental smoking history was not related to initial sensitivity to most effects of nicotine. The main exception was the increase in self-reported “want more” with nicotine dose in those with two versus one or no smoking parents (). Therefore, increased (or decreased) initial sensitivity to nicotine is probably not a key mechanism explaining how parental smoking increases risk of nicotine dependence, although enhancement of “want more” in response to nicotine could be important (O’Connor et al., 2005
). Research should focus on other possible pharmacological mechanisms for the association of smoking risk with parental smoking history, such as in utero exposure to smoking (Buka et al. 2003
) and differential adaptation to chronic
nicotine exposure over time (rather than acute initial sensitivity). Non-pharmacological mechanisms are also plausible, such as smoking parents influencing smoking in offspring by social modeling or increasing their access to cigarettes (Jackson et al. 1997
Among the strengths of this study is the novelty of relating initial nicotine sensitivity to two of the three individual difference factors of interest. Although a few prior studies have examined simple sex differences in initial nicotine sensitivity (e.g., Perkins et al. 1997
), to our knowledge this study is the first to directly test prospectively whether other drug use or parental smoking history influences initial sensitivity to nicotine in humans. Another strength is the prospective assessment of nicotine responses on a variety of measures across multiple response domains, including responses to nicotine other than self-report. Such an approach reduces the potential problem of biased or inaccurate recall inherent in the retrospective self-report of early responses to nicotine via smoking in prior studies of initial sensitivity to nicotine (or smoking), including those assessing parental smoking influences (Hu et al. 2006
; O’Connor et al. 2005
; Pomerleau, et al., 2004
). We also corroborated subject self-report of no or limited tobacco exposure history with reports by friends or family who were familiar with the subjects’ past, eliminating about one in four prospective participants whose reports of minimal tobacco use was not be corroborated. Verification that subjects were naïve to nicotine increases confidence that their responses to acute nicotine administration reflected their initial sensitivity, unaltered by onset of chronic tolerance due to more extensive smoking. Other study strengths include use of controlled doses of nicotine corrected for body weight and use of placebo and more than one dose of nicotine. Use of nicotine delivery via nasal spray isolated effects of nicotine per se
, without the potential confounding effects of the other constituents of tobacco smoke (Pomerleau et al., 1989
This study also had several limitations. Self-report assessment of parental smoking history allowed for the possibility of biased or inaccurate reporting of parental smoking history by participants, although research suggests that such self-report is very reliable (Pomerleau et al., 2005
). The prevalence of ever smoking in the parents of our sample was 56% for fathers and 40% for mothers, roughly comparable to the prevalence of ever smoking in U.S. adults aged 45–64 (54.0% as of 2000; Giovino, 2002
), the age range of most of these parents. The fact that subjects’ other drug use history was determined by self-report is an additional limitation, although objective assessment of each is difficult and subjects had little reason to misrepresent their past marijuana use or current caffeine or alcohol intake, short of alcohol abuse.
We also included young adults, rather than adolescents, due to ethical and practical concerns about giving nicotine to naïve adolescents. Yet, adolescence is the age at which those who become smokers usually experience initial nicotine exposure, and other drug use or parental smoking history may have more influence on nicotine sensitivity at that age. However, there is little reason to assume that individual differences in initial nicotine sensitivity do not “track”, or remain consistent, from adolescence to young adulthood. In another limitation, all of our participants, necessarily, were young adults who had self-selected to their status as nonsmokers. The influence of other drug use and parental smoking history, and perhaps even sex, on nicotine sensitivity may be more prominent within a heterogeneous sample of nicotine-naïve individuals that includes more of those at greater risk for dependence, although how this can be done practically and ethically is uncertain.
In addition, despite some advantages, our nicotine spray administration procedure is also a limitation. Sensitivity to nicotine spray may not relate to sensitivity to nicotine via cigarette smoking, although some research in smokers suggests generally comparable mood and physiological responses to nicotine between these methods (Perkins et al., 1994b
). A more rapid uptake of nicotine by smoking or stimuli accompanying smoking (e.g. taste, smell) but not nasal spray may influence initial sensitivity to nicotine intake by smoking in naive individuals. Furthermore, the doses used were fairly low, to simulate amounts consumed during cigarette experimentation (Eissenberg and Balster, 2000
), i.e. the typical nicotine intake during initial exposure in the natural environment. Cross-tolerance or cross-sensitization with nicotine and the influence of parental smoking history on sensitivity to nicotine may be more apparent in acute testing with larger doses of nicotine, just as we have seen with sex differences in nicotine reinforcement in prior studies (Perkins et al. 1997
In summary, this study found that, prior to the onset of nicotine dependence, men and women may differ in initial sensitivity to some subjective effects of nicotine related to reward or incentive salience but not to most other effects, partly consistent with other research. Sex differences in nicotine reinforcement may be moderated by dose and by other individual differences, such as past use of marijuana. With the exception of a few reward-related measures, neither a history of other drug use nor having parents who smoked, by themselves, appear to be associated with initial nicotine sensitivity. Future research should investigate variability in initial sensitivity to a variety of nicotine responses via other methods of administration, especially cigarette smoking, and in more diverse and younger samples of nonsmokers, where ethically and practically feasible. Results could identify directions for targeting efforts at primary prevention of tobacco use to particularly vulnerable children and adolescents.